Varicella-zoster virus (VZV) is one of the six well-known viruses of the human herpesvirus family, together with herpes simplex virus types I and II, cytomegalovirus, Epstein-Barr virus and human herpesvirus 6. VZV causes chickenpox and herpes zoster. Chickenpox is a normally benign disease that is acquired by most children in developed countries and is characterized by mild systemic effects and the characteristic varicella skin rash. However, it can have significant morbidity and even mortality in neonates and in immunocompromised patients, especially leukemic children. In such patients, complications include widespread visceral dissemination of the virus, varicella pneumonia, and encephalitis. For unknown reasons, chickenpox in adults is often more severe than in children and more likely to have complications. Infection with chickenpox almost always provides life-long immunity to subsequent re-infection.
Herpes zoster, also called shingles, is caused by the reactivation of VZV that has established a latent state in neuronal cells of a ganglion, normally after chickenpox. There are several hundred thousand cases of herpes zoster in the United States annually (Ragozzino et al. (1982), Medicine 61:310-316). About 10-20% of adults will have at least one attack of herpes zoster during their lifetime. Reactivation from the latent state appears to be associated with age-associated weakening of the immune system, as the incidence of herpes zoster increases greatly with age and/or treatment with immunosuppressive drugs. In herpes zoster, the reactivated virus travels down the associated sensory nerve from the ganglion to cause the characteristic varicella lesions in the area of skin (dermatome) innervated by that ganglion, while also causing inflammation of the nerve. The areas supplied by the trigeminal nerve and thoracic ganglia T3 - L2 are most often affected, and about 10-15% of cases have ophthalmic involvement. Zoster is often painful, and the lesions require 2-3 weeks to resolve. Like chickenpox, herpes zoster can become disseminated and have severe complications in immunocompromised patients.
Complications from herpes zoster also frequently occur in immunocompetent patients. At least 10% of such patients develop post-herpetic neuralgia pain continuing after healing of the lesions. The incidence of post-herpetic neuralgia increases sharply with age of the patient, as does the probability that it will last longer than a month. Moreover, as the population ages in developed countries, both the absolute incidence of herpes zoster and of post-herpetic neuralgia can be expected to increase. The neuralgia resolves within 2 months in about 50% of the affected patients and within 1 year in 70-80%, but can last longer in a fraction of patients and can be severe and disabling. The cause of post-herpetic neuralgia is unknown.
Presently available treatments and protective measures against VZV are not entirely satisfactory. A live attenuated vaccine for VZV provides some protection (Takahashi (1986), Pediatrics 78:736-741), but has not yet been approved in the United States. High dose acyclovir speeds recovery from chickenpox, although it is not generally required or recommended in normal children because of possible side-effects. Acyclovir also halts progression and speeds resolution of herpes zoster, but is not known to have any effect on post-herpetic neuralgia. Vidarabine is effective against VZV, but is even more toxic than acyclovir. VZIG, pooled human immunoglobulin with a high titer to VZV, is partially effective in preventing or attenuating subsequent varicella infection when given prophylactically, but it has no effect on established disease (Gershon et al. (1974), N. Eng. J. Med. 290:243-245). Moreover, pooled human collections of polyclonal antibody may also show poor reproducibility of results and create a risk of pathogenic contamination.
The limited effectiveness of human polyclonal sera has led some investigators to attempt to produce human monoclonal antibodies against VZV. Human monoclonals antibodies are advantageous compared with those from mouse or other species, because, inter alia, they exhibit little or no immunogenicity in a human host. However, techniques for producing human antibodies have met with only limited success. For example, immortalization of immunized human lymphocytes with Epstein-Barr virus, while successful in forming monoclonal-antibody secreting cultures, has often failed to produce cells having sufficiently long lifespans to provide a reliable source of the desired antibody. Kozbor et al. (1982), Hybridoma 1:323. In another approach, hybridomas generated by fusion of immunized human lymphoid cell lines with mouse myelomas, have been found to exhibit chromosomal instability. Nowinski et al. (1980), Science 210:537; Lane et al. (1982), J. Exp. Med. 155:133 (1982). Another approach has been described by Ostberg et al. (1983), Hybridoma 2:361-367 and Engelman et al., U.S. Pat. No. 4,634,666. This method entails fusing a mouse myeloma cell with a nonimmunized human B-lymphocyte to form a xenogenic fusion cell. The fusion cell is then fused with an immunized human B-lymphocyte to produce a trioma cell.
With the particular difficulties of producing a human monoclonal antibody compounded by the inherent unpredictability of identifying a first antibody having desirable characteristics against a specific antigen, it is unsurprising that human antibodies produced against VZV to-date have not been shown to possess ideal properties for clinical use. Engelman et al., supra, discuss isolation of two human anti-VZV monoclonal antibodies that exhibit only a low degree of neutralizing activity against the virus (IC.sub.50 of approximately 5 .mu.g/ml). Foung et al. (1985), J. Infec. Diseases 152:280 discuss isolation of two human antibodies to undesignated VZV antigens that also exhibit a low degree of neutralizing activity against the virus (IC.sub.50 of 1 to 5 .mu.g/ml). The complement-dependence and epitope specificity of these antibodies is not reported. Masuho et al., U.S. Pat. No. 4,950,595 discuss isolation of three human monoclonal antibodies against VZV virus. These antibodies exhibited complement-dependent neutralizing activities having IC.sub.50 's ranging from 0.13-6.6 .mu.g/ml. The antibody with the strongest neutralizing activity was reported to bind to the VZV glycoprotein I antigen. Further examples of human monoclonal antibodies against VZV are discussed by Sasaki et al., EP 481089. Although a human monoclonal antibody against the gpIII subunit allegedly showed some potentially useful characteristics, Sasaki et al. report that antibodies against the VZV glycoprotein I and II subunits exhibited only weak neutralizing activity.
Based on the foregoing, it is apparent that a need exists for human monoclonal antibodies exhibiting strong neutralizing activity, particularly complement-independent neutralizing activity, against certain VZV antigens, especially the glycoprotein II (gpII) antigen. The present invention fulfills this and other needs.